Synthetic Applications and Methodological Developments of Donor-Acceptor Cyclopropanes and Related Compounds

Donor-acceptor cyclopropanes are convenient precursors to reactive and versatile 1,3-dipoles, and have found application in the synthesis of a variety of carbo- and heterocyclic scaffolds. This perspective review details our laboratory’s use of donor-acceptor cyclopropanes as intermediates toward the total synthesis of various natural products. We also discuss our work in the development of novel cycloadditions and rearrangements of donor-acceptor cyclopropanes and aziridines, as well as an example of an aryne insertion proceeding via fragmentation of a transient donor-acceptor cyclobutane

Caking behaviour of food powder binary mixes containing sticky and non-sticky powders

Caking of food powders is highly undesirable. Many food powders are powder ingredient mixes and there is little work reported on the caking of food powder mixes. This study focusses on the caking of food powder binary mixes consisting of a “sticky” powder (whey permeate WP or maltodextrin MD) and a “non-sticky” powder (salt, flour or paprika). The powders were exposed to 76% relative humidity to make the WP and MD sticky. Force-displacement testing coupled with visual assessment of 2 particles in contact using a microscope were used to investigate the caking behaviour of the binary mixes. A “sticky” powder mass fraction of at least 20% was required to initiate caking and formation of weak cakes. Increasing percentage “sticky” powder fraction above the initial caking percentage resulted in progressively stronger cakes, however the rate of this progression was much less for the stickiest MD powder. The “non-sticky” powders and how they interacted with the “sticky” powders influenced the caking behaviour of the mix. For example, salt formed the strongest cakes in the WP mixes but formed the weakest in the MD mixes. Ability of a “sticky” powder to deform and flow influenced caking behaviour

Rolofylline, an adenosine A1−receptor antagonist, in acute heart failure

Background: Worsening renal function, which is associated with adverse outcomes, often develops in patients with acute heart failure. Experimental and clinical studies suggest that counterregulatory responses mediated by adenosine may be involved. We tested the hypothesis that the use of rolofylline, an adenosine A1−receptor antagonist, would improve dyspnea, reduce the risk of worsening renal function, and lead to a more favorable clinical course in patients with acute heart failure. Methods: We conducted a multicenter, double-blind, placebo-controlled trial involving patients hospitalized for acute heart failure with impaired renal function. Within 24 hours after presentation, 2033 patients were randomly assigned, in a 2:1 ratio, to receive daily intravenous rolofylline (30 mg) or placebo for up to 3 days. The primary end point was treatment success, treatment failure, or no change in the patient’s clinical condition; this end point was defined according to survival, heart-failure status, and changes in renal function. Secondary end points were the post-treatment development of persistent renal impairment and the 60-day rate of death or readmission for cardiovascular or renal causes. Results: Rolofylline, as compared with placebo, did not provide a benefit with respect to the primary end point (odds ratio, 0.92; 95% confidence interval, 0.78 to 1.09; P=0.35). Persistent renal impairment developed in 15.0% of patients in the rolofylline group and in 13.7% of patients in the placebo group (P=0.44). By 60 days, death or readmission for cardiovascular or renal causes had occurred in similar proportions of patients assigned to rolofylline and placebo (30.7% and 31.9%, respectively; P=0.86). Adverse-event rates were similar overall; however, only patients in the rolofylline group had seizures, a known potential adverse effect of A1-receptor antagonists. Conclusions: Rolofylline did not have a favorable effect with respect to the primary clinical composite end point, nor did it improve renal function or 60-day outcomes. It does not show promise in the treatment of acute heart failure with renal dysfunction. (Funded by NovaCardia, a subsidiary of Merck; ClinicalTrials.gov numbers, NCT00328692 and NCT00354458.

Systolic blood pressure reduction during the first 24 h in acute heart failure admission: friend or foe?

Aims: Changes in systolic blood pressure (SBP) during an admission for acute heart failure (AHF), especially those leading to hypotension, have been suggested to increase the risk for adverse outcomes. Methods and results: We analysed associations of SBP decrease during the first 24 h from randomization with serum creatinine changes at the last time-point available (72 h), using linear regression, and with 30- and 180-day outcomes, using Cox regression, in 1257 patients in the VERITAS study. After multivariable adjustment for baseline SBP, greater SBP decrease at 24 h from randomization was associated with greater creatinine increase at 72 h and greater risk for 30-day all-cause death, worsening heart failure (HF) or HF readmission. The hazard ratio (HR) for each 1 mmHg decrease in SBP at 24 h for 30-day death, worsening HF or HF rehospitalization was 1.01 [95% confidence interval (CI) 1.00–1.02; P = 0.021]. Similarly, the HR for each 1 mmHg decrease in SBP at 24 h for 180-day all-cause mortality was 1.01 (95% CI 1.00–1.03; P = 0.038). The associations between SBP decrease and outcomes did not differ by tezosentan treatment group, although tezosentan treatment was associated with a greater SBP decrease at 24 h. Conclusions: In the current post hoc analysis, SBP decrease during the first 24 h was associated with increased renal impairment and adverse outcomes at 30 and 180 days. Caution, with special attention to blood pressure monitoring, should be exercised when vasodilating agents are given to AHF patients

Predictors and associations with outcomes of length of hospital stay in patients with acute heart failure: results from VERITAS

Background: The length of hospital stay (LOS) is important in patients admitted for acute heart failure (AHF) because it prolongs an unpleasant experience for the patients and adds substantially to health care costs. Methods and Results: We examined the association between LOS and baseline characteristics, 10-day post-discharge HF readmission, and 90-day post-discharge mortality in 1347 patients with AHF enrolled in the VERITAS program. Longer LOS was associated with greater HF severity and disease burden at baseline; however, most of the variability of LOS could not be explained by these factors. LOS was associated with a higher HF risk of both HF readmission (odds ratio for 1-day increase: 1.08; 95% confidence interval [CI] 1.01–1.16; P = .019) and 90-day mortality (hazard ratio for 1-day increase: 1.05; 95% CI 1.02–1.07; P < .001), although these associations are partially explained by concurrent end-organ damage and worsening heart failure during the first days of admission. Conclusions: In patients who have been admitted for AHF, longer length of hospital stay is associated with a higher rate of short-term mortality. Clinical Trial Registration: VERITAS-1 and -2: Clinicaltrials.gov identifiers NCT00525707 and NCT00524433

Anthropometric profiles of elite athletes

Quantifying body composition is central to monitoring performance and training in athletes, however limited sport-specific anthropometric reference data, assessed and reported in a standardised manner, is available. This study provides anthropometric profiles in elite male athletes from different sports. Elite male athletes (n = 73) from National squads of boxing (n = 10), cricket (n = 21), swimming (n = 23), hockey (n = 10) and eventing (n = 9) were assessed for body mass, height, eight skinfolds (triceps, subscapular, biceps, iliac crest, supraspinal, abdominal, thigh and medial calf), body circumferences (arm, waist, hip, thigh and calf) and muscle circumferences (arm, thigh, calf) using ISAK standardised guidelines. For all athletes, large variability exists for measures of skinfold thickness at each skinfold site. Swimming (64.6 ± 16.1 mm) and boxing (63.5 ± 16.1 mm) were similar for the sum of eight skinfolds (Σ8SKF) but swimming had lower Σ8SKF compared to cricket (86.1 ± 21.3 mm; p = .011) and eventing (89.9 ± 30.7 mm; p = .028). Hockey (81.9 ± 26.3 mm) and eventing had the most varied Σ8SKF. Thigh body (p=.006) and muscle circumferences (p = .005) were significantly reduced in boxing compared to hockey. No differences were seen between sports for arm (p = .346; ES = .06) and calf (p = .382; ES = .06) muscle circumferences. The anthropometric profiles for elite athletes from various sports during pre-season training will be a useful resource for sports professionals when monitoring and interpreting body composition data. Large variation exists in anthropometric profiles between the different athletes and different sports, highlighting the necessity to have sport-specific normative ranges available to allow optimal monitoring of individual athletes particularly varying across sports as well as age, training status and position

A network analysis to compare biomarker profiles in patients with and without diabetes mellitus in acute heart failure

Aims: It is unclear whether distinct pathophysiological processes are present among patients with acute heart failure (AHF), with and without diabetes. Network analysis of biomarkers may identify correlative associations that reflect different pathophysiological pathways. Methods and results: We analysed a panel of 48 circulating biomarkers measured within 24 h of admission for AHF in a subset of patients enrolled in the PROTECT trial. In patients with and without diabetes, we performed a network analysis to identify correlations between measured biomarkers. Compared with patients without diabetes (n = 1111), those with diabetes (n = 922) had a higher prevalence of ischaemic heart disease and traditional coronary risk factors. After multivariable adjustment, patients with and without diabetes had significantly different levels of biomarkers across a spectrum of pathophysiological domains, including inflammation (TNFR-1a, periostin), cardiomyocyte stretch (BNP), angiogenesis (VEGFR, angiogenin), and renal function (NGAL, KIM-1) (adjusted P-value <0.05). Among patients with diabetes, network analysis revealed that periostin strongly clustered with C-reactive protein and interleukin-6. Furthermore, renal markers (creatinine and NGAL) closely associated with potassium and glucose. These findings were not seen among patients without diabetes. Conclusion: Patients with AHF and diabetes, compared with those without diabetes, have distinct biomarker profiles. Network analysis suggests that cardiac remodelling, inflammation, and fibrosis are closely associated with each other in patients with diabetes. Furthermore, potassium levels may be sensitive to changes in renal function as reflected by the strong renal–potassium–glucose correlation. These findings were not seen among patients without diabetes and may suggest distinct pathophysiological processes among AHF patients with diabetes

Biomarker profiles of acute heart failure patients with a mid-range ejection fraction

OBJECTIVES: In this study, the authors used biomarker profiles to characterize differences between patients with acute heart failure with a midrange ejection fraction (HFmrEF) and compare them with patients with a reduced (heart failure with a reduced ejection fraction [HFrEF]) and preserved (heart failure with a preserved ejection fraction [HFpEF]) ejection fraction. BACKGROUND: Limited data are available on biomarker profiles in acute HFmrEF. METHODS: A panel of 37 biomarkers from different pathophysiological domains (e.g., myocardial stretch, inflammation, angiogenesis, oxidative stress, hematopoiesis) were measured at admission and after 24 h in 843 acute heart failure patients from the PROTECT trial. HFpEF was defined as left ventricular ejection fraction (LVEF) of ≥50% (n = 108), HFrEF as LVEF of <40% (n = 607), and HFmrEF as LVEF of 40% to 49% (n = 128). RESULTS: Hemoglobin and brain natriuretic peptide levels (300 pg/ml [HFpEF]; 397 pg/ml [HFmrEF]; 521 pg/ml [HFrEF]; ptrend <0.001) showed an upward trend with decreasing LVEF. Network analysis showed that in HFrEF interactions between biomarkers were mostly related to cardiac stretch, whereas in HFpEF, biomarker interactions were mostly related to inflammation. In HFmrEF, biomarker interactions were both related to inflammation and cardiac stretch. In HFpEF and HFmrEF (but not in HFrEF), remodeling markers at admission and changes in levels of inflammatory markers across the first 24 h were predictive for all-cause mortality and rehospitalization at 60 days (pinteraction <0.05). CONCLUSIONS: Biomarker profiles in patients with acute HFrEF were mainly related to cardiac stretch and in HFpEF related to inflammation. Patients with HFmrEF showed an intermediate biomarker profile with biomarker interactions between both cardiac stretch and inflammation markers. (PROTECT-1: A Study of the Selective A1 Adenosine Receptor Antagonist KW-3902 for Patients Hospitalized With Acute HF and Volume Overload to Assess Treatment Effect on Congestion and Renal Function; NCT00328692)

Organic groundwater contamination evaluation and prediction

Adsorption of two organic compounds, Trichloroethylene (TCE) and Pentachlorophenol (PCP), on several Missouri soils were determined. The soils used were of the Coppock, Parsons, Putnam, Grundy and Lebanon series. TCE concentrations were determined by gas chromatography, while PCP concentrations were measured by radio-assay technique. Batch adsorption experiments were conducted using a soil and various organic compound concentrations. It was found that adsorption data for both TCE and PCP fit a Freundlich relationship. TCE and PCP adsorption on Missouri soils decreased with increasing pH. Organic matter in soil was an important parameter in determining the extent of TCE and PCP adsorption. TCE was poorly adsorbed on the soils tested while; PCP adsorption was more strongly adsorbed. This would indicate that TCE would migrate readily with the groundwater, while PCP migration would be somewhat retarded.Project # G852-05 Agreement # 14-08-000

From mantle plume to rift-related volcanism of an oceanic plateau: The complex magmatic evolution of the Rio Grande Rise, South Atlantic

The Rio Grande Rise in the western South Atlantic Ocean has been interpreted as either an oceanic plateau related to the Tristan-Gough mantle plume, or a fragment of detached continental crust. Here we present new major and trace element data for volcanic rocks from the western and eastern Rio Grande Rise and the adjacent Jean Charcot Seamount Chain. The eastern Rio Grande Rise and older parts of the western Rio Grande Rise are comprised of tholeiitic basalt with moderately enriched trace element compositions and likely formed above the Tristan-Gough mantle plume close to the southern Mid-Atlantic Ridge. Younger alkalic lavas from the western Rio Grande Rise and the Jean Charcot Seamount Chain were formed by lower degrees of melting beneath thicker lithosphere in an intraplate setting possibly during rifting of the plateau. There is no clear geochemical evidence that remnants of continental crust are present beneath the Rio Grande Rise